Increased Gluconeogenesis is One Cause of Cystic Fibrosis Related Diabetes (CFRD)

People with CF have a high incidence of diabetes, called CFRD. CFRD is an important cause of
worsened morbidity and mortality, thus understanding the pathophysiology underlying its
development is imperative. Insulin deficiency has been well recognized as one cause of CFRD;
however the clinical presentation and studies of pathogenesis indicate that the etiology is
more complex. There is strong evidence that normal metabolism of carbohydrate, protein and
fat is altered in CF. We believe that the inflammatory response to chronic underlying lung
disease is responsible for insulin resistance and alters substrate metabolism, and that these
changes, in addition to insulin deficiency cause CFRD. Our global hypothesis is that
hyperglycemia is caused, in part, by high rates of gluconeogenesis resulting from excessive
amino acid substrate availability caused by cytokine-mediated protein catabolism. We further
hypothesize that inflammation alters normal fatty acid metabolism leading to lipogenesis, an
energy wasteful pathway. We will recruit 24 adult CF subjects and 10 controls (similar in
distribution in lean tissue mass, age and gender) and will categorize them according to
glucose tolerance (OGTT), as well as insulin secretion and insulin sensitivity using the
Tolbutamide-stimulated IVGTT and the Minimal Model. Clinical status will be characterized by
measuring pulmonary function and modified NIH scores, in addition to measuring levels of
circulating cytokines. Gluconeogenesis (GNG) will be quantified by measuring the
incorporation 2H into the 2nd, 5th and 6th carbons of glucose. Amino acid turnover rates will
be measured using stable isotopes of lactate and alanine and whole body protein turnover
(WBPT) will be measured using [1-13C]leucine and [15N2]urea. Fat metabolism will be evaluated
by measuring ketone body turnover using stable isotopes, and by quantifying lipogenesis using
the isotopomer equilibration method. Key enzymes of fatty acid metabolism will also be
measured. We will utilize indirect calorimetry to measure resting energy expenditure.
Subjects will be recruited from the CF centers at the University of Texas- Southwestern and
the South Central CF Consortium.

Our proposal is intended to better describe the unique metabolism of people with CF, and to
provide a comprehensive evaluation of pathophysiologic changes which contribute to the
development of CFRD and to wasting; and are part of the applicant's long-range goal which is
to identify the underlying causes of CF related diabetes and catabolism so that
disease-specific therapies can be developed. We fully expect that the proposed studies will
provide new and important information.

cystic fibrosis with any type of glucose tolerance